Epilepsy Caused by Brain Tumours - Kate Connor, Trinity College Dublin, Ireland

Brain tumours vary greatly and 30% of them cause an epilepsy to develop - hence the name Brain Tumour Related Epilepsy. Hear more for Brain Tumour Awareness Month from cancer neuroscientist: Kate Connor.

Reported by Torie Robinson | Edited and produced by Pete Allen

Podcast

• Transcription

  00:00 Kate Connor
  “The project that I'm working on at the moment is looking to use a novel type of gene therapy to try and counteract one of the mechanisms the tumours can use to induce seizures.”

  00:13 Torie Robinson
  Fellow homo sapiens! Welcome back to Epilepsy Sparks Insights. March is Brain Tumour awareness month, and around ⅓ of people with a brain tumour or who have had a brain tumour will develop an epilepsy as a result. So, this is perfect timing for us lucky lot to meet a rising star scientist and brain tumour related epilepsy researcher, Kate Connor!
  Please, don’t forget to like, comment and subscribe because your comment and like will help spread awareness and understanding of the epilepsies around the world. And, also, if you learn just one thing from today, let it be that not everyone with an epilepsy is born with that epilepsy. You, your friend, family member, your patients, anybody could develop an epilepsy at any point in their lives.
  Now, onto our aforementioned star, of the week, Kate Connor!

  01:04 Kate Connor
  I am currently a Research Fellow in Trinity College Dublin, and I started my science journey with a chemistry degree. And I studied chemistry because I've always loved… sort of, like, here's a problem and I want to fix it. And I always thought chemistry was kind of like an interesting way to, you know, pursue that. But then I ended up getting into cancer research through my Ph.D., which I did in University College Dublin, and I focused on breast cancer. And while I did enjoy it and obviously I love science and I stuck around, it wasn't my…I didn't find a huge passion in that field of research. And then I went to a conference over in Germany and got really lucky and met this really interesting scientist who ran a group who studied glioblastoma and did neuro-oncology research. And very cheekily asked if I could have a job! So, I got offered a postdoc in the Royal College of Surgeons [in Ireland] working on a project that was trying to design a novel way to treat brain tumours, a novel way to deliver drugs to brain tumours. And then that's where my interest got sparked and I've been working on brain tumours for the last 8 years. And then, most recently I met Mark Cunningham through a project where we were working in collaboration, and I got into the world of Brain Tumour Related Epilepsy and, yeah, I found my new passion. So [I’m] trying to be a cancer neuroscientist now.

  02:23 Torie Robinson
  I've been thinking about this for a very long time. Can you talk about or just give us a brief insight into the variations in types of brain tumours and how they can cause epilepsy, please? Because, I think lots of us just think, oh, it's a lump of skank in your brain and that's it. But it's not that simple, right?

  02:39 Kate Connor
  No, so, I think when you say “Brain tumour” like you're referring to this huge umbrella of types of tumour. So, not only does it change depending on what cell it arises from - so, you have some that are from the… astrocytomas are from the astrocytes, then you've got oligodendrogliomas and they're from the oligodendrocytes - so, there's tons of different types of tumours, but also they have different mutational profiles, they have different growth rates, they respond differently to therapies. So, the most aggressive one that everyone tends to hear about is glioblastoma. So, this is a grade 4 astrocytoma. It's very invasive. It's very hard to treat and has very poor survival rates. And then you have lower grade tumours - so, lower grade gliomas which tend to grow a lot slower and be a little bit less invasive. And, actually, the incidence of epilepsy or seizures is, as we say, inversely correlated to malignancy. So, it tends to be if you have a lower grade tumour, you have more likelihood of developing seizures.

  03:40 Torie Robinson
  What's that, do you know?

  03:41 Kate Connor
  So, it's actually really interesting. So, there's a couple of reasons. And so, I think the stats are: you have about 40% of high grade gliomas have seizures as a first presenting symptom, but in the lower grade, it can be anywhere from 60-90%. And so, some of the theory is that it's the physical tumour, the pressure the tumour is putting on the brain: so, it's very mechanical. But then one of the major factors is what's called an IDH mutation. So, in the lower grade tumours, um, you tend to have a…more frequently have this mutation in IDH where it's really uncommon in the higher grade tumours. And, actually, if you have an IDH mutation in glioblastoma, they don't even consider it a glioblastoma because your survival rate is like, if you have an IDH mutation, your survival rate is about 12-15 years - compared to 12-15 months: it can be significantly different! So, it's a different disease. And one of the theories, is that when you have this mutation (so more frequently in the lower grade), you have a different metabolism within your tumour, and you produce a chemical called 2-HG as part of this different metabolic process. And that 2-HG, chemically, is very similar to the neurotransmitter glutamate. And we know that glutamate causes excitability in neurons. So, the idea is that the tumours are producing this compound - or this molecule - as a side effect of its altered mutation and altered metabolism, which is then acting like glutamate and causing this sort of excitability in the cells! So, it's really very interesting! That's just one of the many reasons! There's also a theory that maybe the slower-growing tumours have more time to cause the destructive processes that result in epilepsy. So, if you've a really fast-growing tumour, maybe you just haven't had the tumour long enough for epilepsy to develop!

  05:43 Torie Robinson
  So, it's almost like the longer the tumour hangs around, the more slowly it grows. It's almost the better it gets at, actually, kind of, affecting the rest of your brain. It's almost like a, is this a bad word to use, but a “higher quality” tumour, because it can do each and everything it wants to, right? Is that bad?!

  05:55 Kate Connor
  Yeah, it's almost a bit more insidious. It's like slow and, you know, subtly growing, but then it's having this impact around it that it only has the time to do so because it's sort of slow and subtly growing. So…

  06:06 Torie Robinson
  I know somebody whose family member had a brain tumour and the family member continued to have seizures after the tumour had been removed. Why does this happen? So, why does a person - rather than solely having…”solely” having seizures - actually, officially then develop epilepsy? Despite the tumour not being there. Why does that happen?

  06:28 Kate Connor
  It's a really good question because this is exactly what proves that it's not just mechanical pressure causing the seizures. Because, when you remove a high-grade tumour, you're never removing all of it. So, these invasive tumours - before you even go in to resect them - have invaded diffusely into the surrounding brain. And so, for example: historically, I think it was in the 40s, there was a surgeon who did a hemispherectomy on a patient who had a high-grade tumour. And, so, they removed one whole hemisphere, which contained the tumour and it grew back in the other hemisphere, which just showed that those cells have infiltrated really distantly sometimes before you even go in for surgery, in like a glioblastoma, for example. And so, the tumour is so… I don't wanna give it credit, but tumours are “smart”, you know? And they have, you know, a lot of mechanisms that they do, to kind of, almost, convince your body to ignore it, but also to change its environment to suit it to grow. So when you have, yeah, you know, it's really, it's really interesting.

  07:31 Torie Robinson
  It sounds like a proper evolution, like, arising from this tumour. It's like “I'm going to sort out my environment so that I can be, so that I can grow!”.

  07:39 Kate Connor
  Yeah, that's exactly it. So, tumours are able to, for example, change the vascularisation around them. So, tumours are really hypoxic (which means they, because they have really high oxygen demands), so they can cause angiogenesis, which causes the growth of new vasculature, which brings them all the nutrients and glucose they need to grow! So, and this is, you know, basically the fact that they can subvert the environment so “smartly” means that the cells that remain - even when you've resected - are still producing all the factors that are capable of producing an epilepsy. So, tumour cells produce loads of what we call cytokines and these are like mediators or molecules involved in inflammation and loads of them are pro-inflammatory. There's loads of other factors which kind of call immune systems to put too close to the environment, and all of these factors together can essentially…the tumour can just continue to happily live in its environment when the bulk of it's gone! You know, there's still tumour cells there doing what they want to do in the surrounding brain tissue!

  08:43 Torie Robinson
  And when a person has a resection of this tissue, why can't all of the tumour be removed?

  08:53 Kate Connor
  It obviously also depends on where in the brain it is. So, but with any invasive tumour; there's no way you can go in and remove single cells that have invaded into that peri… what we call peritumoral area (so, the area around the tumour). And there are mechanisms, or, like, techniques, that the surgeons will use to try improve their extent of resection. So, they have what's called 5-ALA, which is a dye they can give to the patient beforehand and then during surgery, they can apply a light (a UV light), and they'll see where the tumour cells are. Or, there's other dyes, like there's one called fluorescein, which they use. But even still, you can't go in and remove cell by cell, those invasive cells. And, unfortunately, without removing normal brain tissue and potentially causing a deficit for the patient, it's very difficult to remove 100%. And then those remaining cells: there's also the question of “Are you selecting and, like, leaving behind the most aggressive cells?” because they're the invasive ones! And if those, you know, if those are the only ones you're leaving behind, you've selected for a more aggressive tumour afterwards.

  09:57 Torie Robinson - promo
  A quick mention: if you’d like to check out a hilarious, fellow epilepsy podcaster who happens to have brain tumours, an epilepsy, and a really cute service dog named George, then after you’re listened to this episode (obviously 😁) check out the inspirational Landis Wiedner from the What The EF (capital E, capital F - before you ask!) podcast! You can find the link in the description

  10:24 Torie Robinson
  Well, going on from that then, tell us a little bit about your research and what you foresee the future to potentially look like for people with Brain Tumour Related Epilepsy

  10:33 Kate Connor
  Yeah, I think something which - and I was guilty of this as well before I kind of joined Professor Mark Cunningham's group - was that I never really thought about anything except for the tumour cells. I never thought about the fact that these tumour cells are interacting with your neurons and they're communicating with the neurons around them to basically drive their own malignancy, but also induce these terrible side effects and comorbidities, including epilepsy. And so, what I see in the future, is that more cancer biologists are, will move into understanding that the tumour doesn't exist in isolation and that we need to really consider the impact on, first of all, the tumour growth, but also the quality of life of the patients that have this comorbidity and what you see as a seizure is only one tiny drop in the ocean of the impact that this has on a patient's life who also has a brain tumour.
  So, the project that I'm working on at the moment is looking to use a novel type of gene therapy to try and counteract one of the mechanisms the tumours can use to induce seizures. So, we have this, these viral vectors: so you can induce or you can engineer a cell using a lentivirus where it can insert a piece of DNA into a targeted cell, and then you can produce a certain protein using that technique. And what we have, is, we're very interested in how tumours can use glutamate (which is a neurotransmitter) to kind of subvert the environment that it's in and cause an excitability in the neurons nearby, which then results in epilepsy or in a seizure (and then can result in epilepsy). And we have this gene therapy, whereby we hope we can over-express a certain protein and engineer the neurons to, essentially: when they, when they sense glutamate in the environment to not become overexcited. And so, it kind of is like an “off switch” or like a “trip”, you know, those kind of trip wires you have… or a fuse, it's like a fuse! Kind of… [we have] the hope we can, like, insert this into the nearby neurons and stop them from becoming over excited when the tumour produces glutamate.

  12:40 Torie Robinson
  And at what stage are you in this research?

  12:42 Kate Connor
  We have some really, very talented collaborators who have developed these viral vectors and have shown they work in another setting (not in the brain tumour setting). And what we have done is we've established an animal model where we can grow brain tumours [in a manner] what we call “orthotopically”, so which means we put the brain tumour into the brain. So, in the past, a lot of animal work would have been done where they put the tumour into the flank under the skin, which is fine to grow a tumour, but it doesn't give you any of the interactions the tumour has with the cells around it.

  13:14 Torie Robinson
  Right.

  13:15 Kate Connor
  So, we grow these tumours in the brain of the animal and we also can implant these wireless telemetry devices - so, we do, like, EEG on the animals. And so far, what we've done is we've established how we can grow the tumours and monitor the animals for their seizures using these EEG telemetry devices and video monitoring. And then, in the next, like, I'd say, in the next two months, we're going to start with the treatment, and hopefully we can see an impact on the seizure development. So…

  13:43 Torie Robinson
  Wow, how exciting! Well, you must keep us in the loop and let us know where you are with that!

  13:49 Kate Connor
  Thank you very much for having me.

  13:50 Torie Robinson
  A huge thanks to Kate for sharing with us information about brain tumours, Brain Tumour Related Epilepsy, and indeed her exciting research! And, I don’t know about you but I can’t wait to read her paper on this study when it’s released! Again, if you haven’t already, don’t forget to like, comment, and subscribe, and see you next time!

• Chapters

  00:00 Intro

  01:04 Meet Kate Connor

  02:33 What are the types of brain tumour? How/why can they cause epilepsy?

  06:06 Why epilepsy can remain after tumour removal: "smart", evolving tumours!

  08:43 Why can't all of the tumour be removed?

  09:57 Fellow podcaster: Landis Wiedner & George at "What The EF"

  10:33 Brain tumours impacting quality of life

  11:28 Exciting, novel gene therapy research to treat Brain Tumour Related Epilepsy (BTRE)!

  13:50 Conclusion and thanks

• About Kate

  Kate Connor is a cancer-neuroscientist and post-doc Research Fellow at Trinity College Dublin in Ireland, currently focussing on a project studying a novel treatment for Brain Tumour Related Epilepsy.

  Previously, Kate worked as part of a group studying glioblastomas and doing neuro-oncology research.

  Kate studied chemistry at University College Dublin and did her Ph.D. with a focus on the study of the cocaine and amphetamine regulated transcript (CART); an anorectic neuropeptide, previously shown to be involved in breast cancer and small bowel carcinoid tumours.

• Links to Kate

  LinkedIn: kate-connor

  ResearchGate: Kate-Connor-5

  Cunningham Lab: cunninghamlab.org

  Open Access Government: innovative-gene-therapy-approaches-for-brain-tumour-related-epilepsy

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